Effect of inhaled piriprost (U-60, 257) a novel leukotriene inhibitor, on allergen and exercise induced bronchoconstriction in asthma.
The leukotrienes, a group of oxidative metabolites of arachidonic acid, have potent pharmacological actions on human airways. We have investigated the effects of a leukotriene synthesis inhibitor, piriprost (U-60, 257) administered by inhalation on allergen and exercise induced bronchoconstriction in 12 subjects with allergic asthma. Subjects underwent diagnostic challenges with allergen and treadmill exercise to define the strengths of the stimuli required to reduce the FEV1 to about 25% of baseline (PS25). On separate study days subjects inhaled either piriprost 1 mg or vehicle placebo, followed 15 minutes later by the PS25 allergen or exercise. The FEV1 was measured at regular intervals before and after challenge up to 60 minutes. After allergen challenge in six subjects peak expiratory flow (PEF) was measured for the following 20 hours. When compared with placebo, inhalation of piriprost had no significant protective effect on the fall in FEV1 at any time point within 60 minutes of allergen or exercise challenge. In the four subjects with a documented late asthmatic reaction 2-12 hours after allergen challenge piriprost had no protective effect when compared with placebo. In the subjects who recorded PEF over 20 hours after allergen challenge there was no significant difference between piriprost and placebo. Piriprost was appreciably more irritant to the respiratory tract than was placebo. On the assumption that inhaled piriprost was bioavailable in the airways, this study casts doubt on any theory of a pivotal role for leukotrienes in the pathogenesis of acute exercise and allergen induced airway bronchoconstriction in asthma.


Structure and other molecular properties of actinide trichlorides AnCl3 (An = Th-Cm).
The ground-state molecular properties of the trichlorides of light actinides (An = Th-Cm) have been predicted by state-of-the-art quantum chemical calculations. The ground electronic states have been determined by multireference calculations at the CASPT2 level including both scalar and spin-orbit relativistic effects. These studies supported the expected single-configuration character of ThCl3 and CmCl3 with their well-defined 6dσ/7s hybrid and 5f(7) configurations, respectively. In contrast, the intermediate actinides (PaCl3-AmCl3) with partly filled 5f shells have numerous very low-lying excited states and consequently a mixed character of the spin-orbit ground states. Apart from the planar ThCl3 the ground-state molecular geometries proved to be pyramidal with C(3v) symmetry. The gradually decreasing An-Cl bond distances reveal the actinide contraction known for the atomic and ionic radii of these actinide atoms. Other ground-state molecular properties as vibrational frequencies and natural charges have been obtained by density functional theory calculations using the B3LYP exchange-correlation functional in conjunction with small-core relativistic energy-consistent pseudopotentials for the actinides.


[Relationship between atherosclerosis and aging process].
On this paper, author reviews studies on the relationship between atherogenesis and aging. An increase in serum lipid peroxide level increased the number of circulating vascular endothelial cells. This indicates that the free radical is an injury factor for endothelial cells. In addition macrophages discharged the active oxygen upon stimulation and incorporated oxidized low density lipoprotein. These results suggested that macrophages play a main role in the initiation of atheroma formation. A very small dose of H2O2 induced platelet aggregation in vitro. Thrombin has chemotactic and chemokinetic activity for the smooth muscle cell as does fibrinogen, fibronectin and oxidized LDL. Conclusion. These results suggest close association through free radicals between the aging process and atherogenesis.


Measuring asymmetry from high-density 3D surface scans: An application to human faces.
Perfect bilateral symmetry is the optimal outcome of the development of bilateral traits in the absence of developmental perturbations. Any random perturbation in this perfect symmetrical state is called Fluctuating Asymmetry (FA). Many studies have been conducted on FA as an indicator of Developmental Instability (DI) and its possible link with stress and individual quality in general and with attractiveness, health and level of masculinity or femininity in humans. Most human studies of facial asymmetry use 2D pictures and a limited number of landmarks. We developed a protocol to utilize high-density 3D scans of human faces to measure the level of asymmetry. A completely symmetric spatially dense anthropometric mask with paired vertices is non-rigidly mapped on target faces using an Iterative Closest Point (ICP) registration algorithm. A set of 19 manually indicated landmarks were used to validate the mapping precision. The protocol's accuracy in FA calculation is assessed, and results show that a spatially dense approach is more accurate. In addition, it generates an integrated asymmetry estimate across the entire face. Finally, the automatic nature of the protocol provides a great advantage by omitting the tedious step of manual landmark indication on the biological structure of interest.


Deep water running and general practice in primary care for non-specific low back pain versus general practice alone: randomized controlled trial.
There is equivocal evidence regarding the benefits of aquatic aerobic exercise for non-specific chronic low back pain (NSCLBP) in addition to standard care in general practice consisting of education and advice. The purpose of this study was to compare the addition of deep water running (DWR) to standard general practice (GP) on NSCLBP versus GP care alone on pain, physical and mental health and disability. In this single-blind randomised controlled trial, 58 subjects with NSCLBP were recruited from primary care. The control group received GP care consisting of a physician's consultation and educational booklet only. The experimental group received additional 30-min sessions of DWR three times a week for 15 weeks at the individualized aerobic threshold. Measurements were made pre- and post-intervention and at 1-year follow-up. Both groups showed improvement. The difference between treatment effects at longest follow-up of 1 year was -26.0 (-40.9 to -11.1) mm on the VAS (p < 0.05), -2.5 (-5.7 to -0.2) points in RMQ for disability (p < 0.05), 3.3 (10.0 to 24.7) points on physical health in the physical summary component of the Spanish Short Form 12 (SF-12; p < 0.05) and 5.8 (8.6 to 34.7) points on the mental summary component of the SF-12 (p < 0.05), in favour of the DWR group. For patients with NSCLBP, the addition of DWR to GP was more effective in reducing pain and disability than standard GP alone, suggesting the effectiveness and acceptability of this approach with this group of patients.


Impact of recent antibiotics on nasopharyngeal carriage and lower airway infection in Indigenous Australian children with non-cystic fibrosis bronchiectasis.
Indigenous Australian children have increased rates of bronchiectasis. Despite a lack of high-level evidence on effectiveness and antibiotic resistance, these children often receive long-term antibiotics. In this study, we determined the impact of recent macrolide (primarily azithromycin) and β-lactam antibiotic use on nasopharyngeal colonisation, lower airway infection (>10(4) CFU/mL of bronchoalveolar lavage fluid culture) and antibiotic resistance in non-typeable Haemophilus influenzae (NTHi), Streptococcus pneumoniae and Moraxella catarrhalis isolates from 104 Indigenous children with radiographically confirmed bronchiectasis. Recent antibiotic use was associated with significantly reduced nasopharyngeal carriage, especially of S. pneumoniae in 39 children who received macrolides [odds ratio (OR)=0.22, 95% confidence interval (CI) 0.08-0.63] and 26 children who received β-lactams (OR=0.07, 95% CI 0.01-0.32), but had no significant effect on lower airway infection involving any of the three pathogens. Children given macrolides were significantly more likely to carry (OR=4.58, 95% CI 1.14-21.7) and be infected by (OR=8.13, 95% CI 1.47-81.3) azithromycin-resistant S. pneumoniae. Children who received β-lactam antibiotics may be more likely to have lower airway infection with β-lactamase-positive ampicillin-resistant NTHi (OR=4.40, 95% CI 0.85-23.9). The risk of lower airway infection by antibiotic-resistant pathogens in children receiving antibiotics is of concern. Clinical trials to determine the overall benefit of long-term antibiotic therapy are underway.


Systolic hypertension in arteriosclerosis obliterans of the lower limbs.
Hemodynamic parameters were measured in 24 patients with arteriosclerosis obliterans of the lower limbs (AOLL) in comparison with 16 normal subjects of same age. Systemic artérial compliance was estimated from a simple visco-elastic model. In patients with (AOLL), systolic pressure was significantly increased (P less than 0.001) while diastolic pressure remained within normal ranges. Arterial compliance was reduced (P less than 0.01) and was negatively correlated with systolic pressure (r = - 0.72). Intravenous administration of nitroglycerin significantly decreased systolic pressure (P less than 0.05) and increased arterial compliance (P less than 0.01) without any change in mean arterial pressure. The study provided evidence that, in patients with AOLL the reduced systemic arterial compliance contributes in the increase in systolic pressure largely.


A technique to examine phasic thermoregulation during human sleep.
A technique for inducing cyclic skin temperature changes during sleep is described. Stimulation of the facial area induces relatively localized skin temperature responses in the fingers. This centrally mediated response can be used to efficiently probe thermal regulation during sleep. Sleep and skin temperature results from three volunteers support the validity and feasibility of the technique.


[In vitro expansion of the adult human bone marrow mesenchymal stem cells for clinic application in HSCT].
This study was aimed to investigate the efficiency of 4 different culture media for in vitro culture and expanding adult human bone marrow mesenchymal stem cells (ahBM-MSCs) so as to establish a protocol of culturing and expanding hBM-MSCs and provide exprimental basis for hematopoietic blood stem cell transplantation combined with BM-MSCs. BM-MSCs were obtained from 16 fresh adult human bone marrow aspirate by gradient centrifugation with Ficoll Paque, then cultured in DMEM/F12 with 10% umbilical cord blood serum, 10% fetal calf serum (FCS), human blood serum, and MesenCult culture medium. The surface antigens of BM-MSCs were detected by flow cytometry. BM-MSCs were differentiated into osteoblasts and adipocytes under culture in the conditioned medium special for osteogenesis, and adipogenesis and the differentiated MSCs were identified by morphological observation, immunophenotype and immunohistochemical staining. The results showed that BM-MSCs could be isolated from adult human bone marrow and cultured by all culture media. The effect of umbilical cord blood serum on BM-MSC proliferation and their purity were similar to that of MesenCult culture medium, but better than that of FCS and human blood serum. The positive rate of CD29, CD73, CD105 on BM-MSCs cultured in umbilical cord serum and MesenCult medium was higher than that in FCS and adult human serum (p < 0.05), and the positive rate of CD31 was lower than that in FCS and adult human serum (p < 0.05). The positive rate of BM-MSCs differentiated into osteoblasts and adipocytes under culture in the conditioned medium for osteogenesis and adipogenesis with umbilical cord blood serum and MesenCult culture medium was also higher than that in FCS and adult human serum (p < 0.05). It is concluded that BM-MSCs can be obtained by all the four methods. DMEM/F12 with 10% umbilical cord blood serum and MesenCult culture medium are better than the others for the purification and differentiation potency of BM-MSCs in vitro. The medium with umbilical cord serum is valuable for clinical application in HSCT.


Clinical features of headache at altitude: a prospective study.
Headache is the most common nervous system complication at altitude; however, there have been few attempts to characterize clinical features of high-altitude headaches (HAH). To measure prospectively the incidence of HAH and to determine its risk factors and characteristics. Members of an expedition to Kanchenjunga base camp in Nepal (5,100 m) were prospectively studied. Subjects were interviewed prior to the trip and while trekking recorded headaches experienced at >3,000 m using a structured questionnaire incorporating International Headache Society (IHS) and acute mountain sickness (AMS) criteria. In addition, clinical features of headaches in 19 trekkers in other groups above 3,000 m were recorded using the same questionnaire. Eighty-three percent (50/60) reported at least 1 HAH (median 2, range 0 to 10). Those who developed HAH were younger (p = 0.04); women and persons with headaches in daily life were more likely to report severe headaches (p = 0.03 and p = 0.07). One hundred thirty-eight HAH, experienced by 69 persons, are described. The mean altitude at which headaches occurred was 4,723 m. Twenty-six percent of headaches woke subjects at night or occurred upon awakening. HAH reported by migraineurs were accompanied by more phonophobia (p = 0.008). There were no IHS accompanying symptoms in 44% of headaches or symptoms of AMS in 52% of headaches. Headaches are a frequent complication of ascent to altitude. Older age appears to offer some protection, whereas headaches were more severe in women and persons with headaches in daily life. There is a wide clinical spectrum, with some suggesting intracranial hypertension. There is a need for evidence-based diagnostic criteria for headaches at altitude.


Demonstration of agglutinating antibodies against Vibrio parahaemolyticus in the yellow tail flounder (Limanda ferruginea).
Sera from the salt water fish (Yellow tail flounder) and the fresh water fish (rainbow trout) were tested for the presence of circulating antibodies against nine strains of Vibrio parahaemolyticus and one of V. alginolyticus. Thirteen out of 26 flounder sera tested gave agglutinating reactions against one specific strain of V. parahaemolyticus; strain No. 3525. Seven rainbow trout sera tested failed to agglutinate any of the strains tested. All agglutinating activity was lost upon boiling the antigen, therefore, the fish antibodies are due to surface antigens (K-antigens) and not to somatic antigens. The specific V. parahaemolyticus strain No. 3525 belongs to the serological type 03:K30, which might be common to the sea waters of the Eastern United States. The possibility that fish serve as a reservoir to Vibrio parahaemolyticus and its possible implication in the transmission of human disease are discussed.


Psychometric properties of the General Self-Efficacy Scale in Parkinson's disease.
This study aimed to investigate the psychometric properties of the General Self-Efficacy Scale (GSE) in people with Parkinson's disease (PD). More specifically, we investigated data completeness, scaling assumptions, targeting, reliability, and construct validity. This study involves data available from two different projects that included people diagnosed with PD for at least 1 year, yielding two samples (1 and 2). The combined total sample (N=346; 60% men) had a mean (SD) age and PD duration of 71 (8.9) and 9 years (6.3), respectively. Both samples received a self-administered survey by mail, which was administered twice in sample 2. Additional data (e.g., clinical assessments) were available for Sample 1. Total GSE scores were computable for 336 participants (97%). Corrected item-total correlations exceeded 0.4. Principal component analyses identified one component (the eigenvalue of the first component extracted was 6.9), explaining 69% of the total variance. Floor and ceiling effects were <6%. Internal consistency (coefficient alpha) was 0.95. Analyses of test-retest reliability yielded (ICC) values from 0.69 to 0.80. The highest value refers to those (n=47) with identical self-ratings of mobility (in the on condition) at both tests; the standard error of measurement was 3.1 points. Construct validity was further supported by correlations in accordance with a priori expectations. This study provides support for the validity and reliability of GSE scores in people with PD; the GSE can thus serve as a valuable outcome measurement in clinical practice and research.


Does your facility have a pediatric sedation team? If not, why not?
Children's hospitals across the country should consider the formation of pediatric sedation teams (PSTs) for both in-patient and outpatient pediatric procedures. As specialization increases and parents become more in-tune to available options, teams that focus on the alleviation of pain and providing a more pleasant procedural experience will become increasingly important to parents when choosing a facility. Regarding facility benefits, PSTs can assist to improve both patient and parent satisfaction, and allow for the relocation of procedures to ambulatory care settings or alternative pediatric inpatient suites. PSTs can also improve cost effectiveness when sedation is involved by decreasing the overall length of stay in procedure rooms and recovery areas, decreasing complications related to less experienced providers of pediatric sedation, and also decreasing incomplete procedure rates. Parents can be attracted by such specialized teams, viewing them as a sign of organizational excellence in the care of children's health.


Photoisomerisation in Aminoazobenzene-Substituted Ruthenium(II) Tris(bipyridine) Complexes: Influence of the Conjugation Pathway.
Transition-metal complexes containing stimuli-responsive systems are attractive for applications in optical devices, photonic memory, photosensing, as well as luminescence imaging. Amongst them, photochromic metal complexes offer the possibility of combining the specific properties of the metal centre and the optical response of the photochromic group. The synthesis, the electrochemical properties and the photophysical characterisation of a series of donor-acceptor azobenzene derivatives that possess bipyridine groups connected to a 4-dialkylaminoazobenzene moiety through various linkers are presented. DFT and TD-DFT calculations were performed to complement the experimental findings and contribute to their interpretation. The position and nature of the linker (ethynyl, triazolyl, none) were engineered and shown to induce different electronic coupling between donor and acceptor in ligands and complexes. This in turn led to strong modulations in terms of photoisomerisation of the ligands and complexes.


[Rectus sheath haematoma--rare complication of anticoagulant therapy].
The haematoma in the sheath of musculus rectus abdominis is a rare clinical entity. Its diagnosis is often difficult. Authors observed it in three patients who were on anticoagulant therapy. All subjects were female; two of them had decreased renal function. All three patients received thrombocyte aggregation inhibitor therapy as well. The anticoagulant treatment (low molecular weight heparin in two cases, warfarin in one case) caused excessive anticoagulant effect. The diagnosis, which could be suspected after the physical examination, was established in two cases by ultrasonography and in one case by computed tomography. Two patients were surgically treated while the third patient was healed with conservative treatment. To prevent the rectus sheath haematoma, authors suggest a particularly careful control of anticoagulant treatment in older females and in subjects with decreased renal function, especially if the patient takes thrombocyte aggregation inhibitors, too.


Susceptibility testing of anaerobic bacteria: myth, magic, or method?
The demand for susceptibility testing of anaerobes has increased, yet consensus as to procedure and interpretation in this area has not been achieved. While routine testing of anaerobic isolates is not needed, certain isolates in specific clinical settings should be tested. Also, laboratories may monitor their local antibiograms by doing periodic surveillance batch testing. The National Committee for Clinical Laboratory Standards has published a protocol of methods approved for susceptibility testing of anaerobic bacteria. Both agar and broth microdilution are included; however, the broth disk elution method is no longer approved by the National Committee for Clinical Laboratory Standards because of method-related interpretive errors. A number of newer methods are undergoing evaluation and seem promising. Clinicians and microbiologists reviewing susceptibility reports should be aware of sources of variability in the test results. Variables in susceptibility testing of anaerobes include the media and methods used, organisms chosen for testing, breakpoints chosen for interpretation, antibiotic, and determination of endpoint. Clustering of MICs around the breakpoint may lead to significant variability in test results. Adherence of testing laboratories to approved methods and careful descriptions of the method and the breakpoints used for interpretation would facilitate interlaboratory comparisons and allow problems of emerging resistance to be noted. A variety of resistance mechanisms occurs in anaerobic bacteria, including the production of beta-lactamase and other drug-inactivating enzymes, alteration of target proteins, and inability of the drug to penetrate the bacterial wall. Antimicrobial resistance patterns in the United States and abroad are described.


Quantitative analysis of synchrotron radiation intravenous angiographic images.
A medical research protocol on clinical intravenous coronary angiography has been completed at the European Synchrotron Radiation Facility (ESRF) biomedical beamline. The aim was to investigate the accuracy of intravenous coronary angiography based on the K-edge digital subtraction technique for the detection of in-stent restenosis. For each patient, diagnosis has been performed on the synchrotron radiation images and monitored with the conventional selective coronary angiography method taken as the golden standard. In this paper, the methods of image processing and the results of the quantitative analysis are described. Image processing includes beam harmonic contamination correction, spatial deconvolution and the extraction of a 'contrast' and a 'tissue' image from each couple of radiograms simultaneously acquired at energies bracketing the K-edge of iodine. Quantitative analysis includes the estimation of the vessel diameter, the calculation of the absolute iodine concentration profiles along the coronary arteries and the stenosis degree measurement.


Civil-Military Collaboration to Facilitate Rapid Deployment of a Mobile Laboratory in Early Response to COVID-19: A High-Readiness Exercise.
Rapid and adaptable diagnostic capabilities are of great importance in the face of emerging infectious diseases. In an outbreak, timely establishment of diagnostic routines is crucial to identifying cases and preventing the spread of the disease, especially when faced with high-consequence pathogens. In this article, we describe a multiagency exercise including the rapid deployment and diagnostic adaptation of the Swedish Armed Forces mobile laboratory (biological field analysis laboratory) in the context of COVID-19. This deployment was initiated as a high-readiness exercise at the end of January 2020, when the global development of the outbreak was still uncertain. Through collaboration with the Public Health Agency of Sweden and a civilian hospital, a real-time reverse transcriptase polymerase chain reaction method specific to SARS-CoV-2 was made available and adapted to the mobile laboratory, and the team established and evaluated a functional and efficient diagnostic asset along with a logistical support chain. We also organized and evaluated mobile testing teams, and the method was later used in large-scale, national, cross-sectional COVID-19 surveys in several regions of Sweden. In this article, we focus on the challenges of overbridging the civil-military interface in this context and identifying lessons learned and added values to the response during the early pandemic. We propose that the experiences from this exercise and governmental agency collaboration are valuable in preparation for future outbreaks.


Control of central and peripheral tolerance by Aire.
The negative selection of self-reactive thymocytes depends on the expression of tissue-specific antigens by medullary thymic epithelial cells. The autoimmune regulator (Aire) protein plays an important role in turning on these antigens, and the absence of even one Aire-induced tissue-specific antigen in the thymus can lead to autoimmunity in the antigen-expressing target organ. Recently, Aire protein has been detected in peripheral lymphoid organs, suggesting that peripheral Aire plays a complementary role here. In these peripheral sites, Aire was found to regulate the expression of a group of tissue-specific antigens that is distinct from those expressed in the thymus. Furthermore, transgenic antigen expression in extrathymic Aire-expressing cells (eTACs) can mediate deletional tolerance, but the immunological relevance of Aire-dependent, endogenous tissue-specific antigens remains to be determined.


Zinc transporters belonging to the Cation Diffusion Facilitator (CDF) family have complementary roles in transporting zinc out of the cytosol.
Zinc is an essential trace element that is required for the function of a large number of proteins. As these zinc-binding proteins are found within the cytosol and organelles, all eukaryotes require mechanisms to ensure that zinc is delivered to organelles, even under conditions of zinc deficiency. Although many zinc transporters belonging to the Cation Diffusion Facilitator (CDF) families have well characterized roles in transporting zinc into the lumens of intracellular compartments, relatively little is known about the mechanisms that maintain organelle zinc homeostasis. The fission yeast Schizosaccharomyces pombe is a useful model system to study organelle zinc homeostasis as it expresses three CDF family members that transport zinc out of the cytosol into intracellular compartments: Zhf1, Cis4, and Zrg17. Zhf1 transports zinc into the endoplasmic reticulum, and Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. Here we have used the high and low affinity ZapCY zinc-responsive FRET sensors to examine cytosolic zinc levels in yeast mutants that lack each of these CDF proteins. We find that deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency, whereas deletion of zhf1 results in zinc accumulating in the cytosol when zinc is not limiting. We also show that the expression of cis4, zrg17, and zhf1 is independent of cellular zinc status. Taken together our results suggest that the Cis4/Zrg17 complex is necessary for zinc transport out of the cytosol under conditions of zinc-deficiency, while Zhf1 plays the dominant role in removing zinc from the cytosol when labile zinc is present. We propose that the properties and/or activities of individual CDF family members are fine-tuned to enable cells to control the flux of zinc out of the cytosol over a broad range of environmental zinc stress.


Desulfurella amilsii sp. nov., a novel acidotolerant sulfur-respiring bacterium isolated from acidic river sediments.
A novel acidotolerant and moderately thermophilic sulfur-reducing bacterium was isolated from sediments of the Tinto River (Spain), an extremely acidic environment. Strain TR1T stained Gram-negative, and was obligately anaerobic, non-spore-forming and motile. Cells were short rods (1.5-2 × 0.5-0.7 μm), appearing singly or in pairs. Strain TR1T was catalase-negative and slightly oxidase-positive. Urease activity and indole formation were absent, but gelatin hydrolysis was present. Growth was observed at 20-52 °C with an optimum close to 50 °C, and a pH range of 3-7 with optimum between pH 6 and 6.5. Yeast extract was essential for growth, but extra vitamins were not required. In the presence of sulfur, strain TR1T grew with acetate, formate, lactate, pyruvate, stearate, arginine and H2/CO2. All substrates were completely oxidized and H2S and CO2 were the only metabolic products detected. Besides elemental sulfur, thiosulfate was used as an electron acceptor. The isolate also grew by disproportionation of elemental sulfur. The predominant cellular fatty acids were saturated components: C16 : 0, anteiso-C17 : 0 and C18 : 0. The only quinone component detected was menaquinone MK-7(H2). The G+C content of the genomic DNA was 34 mol%. The isolate is affiliated to the genus Desulfurella of the class Deltaproteobacteria, sharing 97 % 16S rRNA gene sequence similarity with the four species described in the genus Desulfurella. Considering the distinct physiological and phylogenetic characteristics, strain TR1T represents a novel species within the genus Desulfurella, for which the name Desulfurella amilsii sp. nov. is proposed. The type strain is TR1T ( = DSM 29984T = JCM 30680T).


[Successful treatment of a mucous membrane pemphigoid in a young dog].
Mucous membrane pemphigoid was diagnosed in a 2.5-year-old male intact foxhound-beagle cross which was presented with an acute onset of non-pruritic, multifocal, slowly progressive erosive-ulcerative dermatitis predominantly affecting the nasal planum, eyelids and muzzle with multiple vesicles on the inner pinnae, oral mucosa and tongue. The diagnosis was based on clinical signs and histological examination of skin biopsies. The patient did not respond to immunosuppressive prednisolone therapy, but went into complete remission with oral doxycycline and niacinamide and stayed in remission on long-term exclusive niacinamide treatment.


Biocompatible conjugated polymer nanoparticles labeled with 225Ac for tumor endoradiotherapy.
Recently, endoradiotherapy based on actinium-225 (225Ac) has attracted increasing attention, which is due to its α particles can generate maximal damage to cancer cells while minimizing unnecessary radiation effects on healthy tissues. Herein, 111In/225Ac-radiolabeled conjugated polymer nanoparticles (CPNs) coated with amphiphilic polymer DSPE-PEG-DOTA have been developed as a new injectable nano-radiopharmaceuticals for cancer endoradiotherapy under the guidance of nuclear imaging. Single photon emission computed tomography/computed tomography (SPECT/CT) using 111In-DOTA-PEG-CPNs as nano probe indicates a prolonged retention of radiolabeled nanocarriers, which was consistent with the in vivo biodistribution examined by direct radiometry analysis. Significant inhibition of tumor growth has been observed in murine 4T1 models treated with 225Ac-DOTA-PEG-CPNs when compared to mice treated with PBS or DOTA-PEG-CPNs. The 225Ac-DOTA-PEG-CPNs group experienced no single death within 24 days with the median survival considerably extended to 35 days, while all the mice treated with PBS or DOTA-PEG-CPNs died at 20 days post injection. Additionally, the histopathology studies demonstrated no obvious side effects on healthy tissues after treatment with 225Ac-DOTA-PEG-CPNs. All these results reveal that the new 225Ac-labeled DOTA-PEG-CPNs is promising as paradigm for endoradiotherapy.


A GH115 α-glucuronidase from Schizophyllum commune contributes to the synergistic enzymatic deconstruction of softwood glucuronoarabinoxylan.
Lignocellulosic biomass from softwood represents a valuable resource for the production of biofuels and bio-based materials as alternatives to traditional pulp and paper products. Hemicelluloses constitute an extremely heterogeneous fraction of the plant cell wall, as their molecular structures involve multiple monosaccharide components, glycosidic linkages, and decoration patterns. The complete enzymatic hydrolysis of wood hemicelluloses into monosaccharides is therefore a complex biochemical process that requires the activities of multiple degradative enzymes with complementary activities tailored to the structural features of a particular substrate. Glucuronoarabinoxylan (GAX) is a major hemicellulose component in softwood, and its structural complexity requires more enzyme specificities to achieve complete hydrolysis compared to glucuronoxylans from hardwood and arabinoxylans from grasses. We report the characterisation of a recombinant α-glucuronidase (Agu115) from Schizophyllum commune capable of removing (4-O-methyl)-glucuronic acid ((Me)GlcA) residues from polymeric and oligomeric xylan. The enzyme is required for the complete deconstruction of spruce glucuronoarabinoxylan (GAX) and acts synergistically with other xylan-degrading enzymes, specifically a xylanase (Xyn10C), an α-l-arabinofuranosidase (AbfA), and a β-xylosidase (XynB). Each enzyme in this mixture showed varying degrees of potentiation by the other activities, likely due to increased physical access to their respective target monosaccharides. The exo-acting Agu115 and AbfA were unable to remove all of their respective target side chain decorations from GAX, but their specific activity was significantly boosted by the addition of the endo-Xyn10C xylanase. We demonstrate that the proposed enzymatic cocktail (Agu115 with AbfA, Xyn10C and XynB) achieved almost complete conversion of GAX to arabinofuranose (Araf), xylopyranose (Xylp), and MeGlcA monosaccharides. Addition of Agu115 to the enzymatic cocktail contributes specifically to 25 % of the conversion. However, traces of residual oligosaccharides resistant to this combination of enzymes were still present after deconstruction, due to steric hindrances to enzyme access to the substrate. Our GH115 α-glucuronidase is capable of finely tailoring the molecular structure of softwood GAX, and contributes to the almost complete saccharification of GAX in synergy with other exo- and endo-xylan-acting enzymes. This has great relevance for the cost-efficient production of biofuels from softwood lignocellulose.


Spin-polarised electrons in a one-magnet-only Mott spin junction.
The current flowing through a Mott spin junction depends on the relative spin orientation of the two ferromagnetic layers comprising the "source" and "drain" sides of the junction. The resulting current asymmetry is detected as giant or tunnelling magnetoresistance depending on whether the two ferromagnets are separated by a metal or an insulator. Based on the fundamental principles of reciprocity for spin-dependent electron scattering, one can envisage a one-magnet-only spin junction in which the source is non-magnetic, and the spin information is encoded by the spin polarisation of the electrons that have crossed or are backscattered from the drain magnetic layer. The practical significance of using an unpolarised source is that the state of the magnetic layer can be modified without affecting the process of probing it. Whether this reciprocity is realised in the actual junctions is not yet known. Here, we demonstrate a nano-sized, one-magnet-only Mott spin junction by measuring the finite spin polarisation of the backscattered electrons. Based on this finding, we conclude that since the junction acts as a spin filter, the magnetic layer must experience a spin transfer that could become detectable in view of the high current densities achievable in this technology.


Multi-wavelength light emitting diode-based disposable optrode array for in vivo optogenetic modulation.
We present a light emitting diode (LED)-based optical waveguide array that can optogenetically modulate genetically targeted neurons in the brain. The reusable part of the system consists of control electronics and conventional multi-wavelength LED. The disposable part comprises optical fibers assembled with microlens array fabricated on a silicon die. Both parts can be easily assembled and separated by snap fit structure. Measured light intensity is 3.35 mW/mm2 at 469 nm and 0.29 mW/mm2 at 590 nm when the applied current is 80 mA. In all the tested conditions, the light-induced temperature rise is under 0.5°C and over 90% of the relative light intensity is maintained at 2 mm-distance from the fiber tips. We further tested the efficiency of the optical array in vivo at 469 nm. When the optical array delivers light stimulation on to the visual cortex of a mouse expressing channelrhodopsin-2, the neural activity is significantly increased. The light-driven neural activity is successfully transformed into a percept of the mouse, showing significant learning of the task detecting the cortical stimulation. Our results demonstrate that the proposed optical array interfaces well with the neural circuits in vivo and the system is applicable to guide animal behaviors.


Anacardic Acids from Cashew Nuts Prevent Behavioral Changes and Oxidative Stress Induced by Rotenone in a Rat Model of Parkinson's Disease.
Anacardic acids (AAs) are alkyl phenols mainly presenting in cashew nuts. The antioxidant effects of these compounds have been an area of interest in recent research, with findings suggesting potential therapeutic use for certain diseases. Nevertheless, none of these studies were performed in order to test the hypothesis of whether anacardic acids are capable of preventing behavioral changes and oxidative stress induced by the pesticide rotenone in experimental model of Parkinson's disease. In our research, adult male rats were treated orally with AAs (1, 3, 10, 25, 50, or 100 mg/kg/day) 1 h before rotenone (3 mg/kg; s.c.) for five consecutive days. The behavioral testing strategies, including tests for general locomotor activity (open field), motor coordination (rotarod), and spatial memory performance (elevated T-maze), were carried out. Lipoperoxidation levels and total superoxide dismutase (t-SOD) activity, as well as cytoplasmic and mitochondrial SOD gene expression, were assessed in the substantia nigra (SN), striatum, and cerebral cortex. The results showed that AAs dose-dependently prevented the rotenone-induced learning and motor impairment from 10 mg/kg/day. AAs also precluded rotenone-induced lipoperoxidation in all doses, acting directly on the mitochondria, and improved the t-SOD activity in the doses 25-100 mg/kg/day. AAs per se (100 mg/kg/day) increased SOD gene expression and t-SOD activity. Our findings indicate that the oral administration of AAs prevents rotenone-induced behavioral changes and oxidative stress, in part due to a modulatory action on the mitochondria and SOD gene expression. These data suggest that AAs have promising neuroprotective action against degenerative changes in Parkinson's disease.


[Local electromagnetic hyperthermia in treating patients with chronic prostatitis].
Local electromagnetic hyperthermia (LEH) was applied to 29 patients with nonspecific chronic prostatitis, using UHF-units Plot or Yakhta-3 (915 MHz). Heating was achieved with the help of intracavitary areals via the rectum. A therapeutic course consisted of 6-10 LEH sessions. A direct positive clinical effect was observed in all the patients after the LEH course was over. Prostatic secretion indices returned to normal in 25 patients; a moderate leucocyte count was found in 4 patients only. Exacerbation of disease was noted in 3 patients in the course of the first year after therapy. They were given a repeated LEH course, which brought about a positive effect. Potency in 14 patients (8 of 10 with decreased potency and 6 with normal potency) was increased after LEH. LEH seems to hold promise for therapy of chronic prostatitis and its consequences. This method results in no complications, therefore LEH courses can be repeated in case of exacerbation.


[Comparative evaluation of the effectiveness of different treatment methods of atrial fibrillation in thyrotoxicosis patients].
Comparative data are presented on the treatment of auricular fibrillation in 105 patients with severe thyrotoxicosis. All the patients were divided into 3 groups to evaluate the effectiveness of the treatment: the 1st group of 45 patients, given complex therapy (mercazolyl, diiodotyrosine, cardiac glycosides, potassium drugs, ATF, cocarboxylase); the 2nd group of 40 subjects, treated with inderal in a dose of 80 to 120 mg during 7 days, followed by complex therapy; the 3d group of patients given complex therapy and cordaron. The latter combined with complex therapy was the most effective method in the treatment of auricular fibrillation in patients who suffered from thyrotoxicosis. In 15 of 20 patients of the 3d group the sinus rhythm was recovered. The treatment effectiveness in this group of patients was not dependent on their age, thyrotoxicosis and arrhythmia duration and the degree of circulatory disturbance, whereas in patients of the 1st group good results, as a rule, were seen in young and middle-aged subjects with the disease duration, not exceeding one year and circulation disorder of the Ist and IInd stages. It is concluded that in pathogenesis of auricular fibrillation the main role belongs to the unfavourable effect of excessive thyroid hormones upon the metabolic processes in myocardial auricles.


A Three Revolute-Revolute-Spherical Wearable Fingertip Cutaneous Device for Stiffness Rendering.
We present a novel three Revolute-Revolute-Spherical (3RRS) wearable fingertip device for the rendering of stiffness information. It is composed of a static upper body and a mobile end-effector. The upper body is located on the nail side of the finger, supporting three small servo motors, and the mobile end-effector is in contact with the finger pulp. The two parts are connected by three articulated legs, actuated by the motors. The end-effector can move toward the user's fingertip and rotate it to simulate contacts with arbitrarily-oriented surfaces. Moreover, a vibrotactile motor placed below the end-effector conveys vibrations to the fingertip. The proposed device weights 25 g for 35 x 50 x 48 mm dimensions. To test the effectiveness of our wearable haptic device and its level of wearability, we carried out two experiments, enrolling 30 human subjects in total. The first experiment tested the capability of our device in differentiating stiffness information, while the second one focused on evaluating its applicability in an immersive virtual reality scenario. Results showed the effectiveness of the proposed wearable solution, with a JND for stiffness of 208.5 17.2 N/m. Moreover, all subjects preferred the virtual interaction experience when provided with wearable cutaneous feedback, even if results also showed that subjects found our device still a bit difficult to use.


In-depth performance analysis of an EEG based neonatal seizure detection algorithm.
To describe a novel neurophysiology based performance analysis of automated seizure detection algorithms for neonatal EEG to characterize features of detected and non-detected seizures and causes of false detections to identify areas for algorithmic improvement. EEGs of 20 term neonates were recorded (10 seizure, 10 non-seizure). Seizures were annotated by an expert and characterized using a novel set of 10 criteria. ANSeR seizure detection algorithm (SDA) seizure annotations were compared to the expert to derive detected and non-detected seizures at three SDA sensitivity thresholds. Differences in seizure characteristics between groups were compared using univariate and multivariate analysis. False detections were characterized. The expert detected 421 seizures. The SDA at thresholds 0.4, 0.5, 0.6 detected 60%, 54% and 45% of seizures. At all thresholds, multivariate analyses demonstrated that the odds of detecting seizure increased with 4 criteria: seizure amplitude, duration, rhythmicity and number of EEG channels involved at seizure peak. Major causes of false detections included respiration and sweat artefacts or a highly rhythmic background, often during intermediate sleep. This rigorous analysis allows estimation of how key seizure features are exploited by SDAs. This study resulted in a beta version of ANSeR with significantly improved performance.


Building successful coalitions for promoting advance care planning.
Advance care planning (ACP) has had few successful initiatives. This qualitative study explores the challenges and successes of an advance care planning coalition in Wisconsin called Life Planning 2000 using key informant interviews (n = 24) and grounded theory. Major themes included: commitment (the need for leadership, recruitment of key members, and funding); cohesiveness (disparate groups collaborating toward a common purpose), and outcomes (shift in paradigm from signing documents to process of advanced care planning, new-found collaborative relationships, and educational tool development). Coalitions need to define short-, intermediate-, and long-term goals that result in measurable outcomes and an evaluation process. Resources must be commensurate with goals. Strong leadership, paid staff adequate funding, and the collaboration of diverse groups working toward common goals are the basic requirements of a successful coalition.


Perifollicular linear projections: A dermatoscopic criterion for the diagnosis of lentigo maligna on the face.
Lentigo maligna (LM) can mimic benign, flat, pigmented lesions and can be challenging to diagnose. To describe a new dermatoscopic feature termed "perifollicular linear projections (PLP)" as a diagnostic criterion for LM on the face. Retrospective study on reflectance confocal microscopy and dermatoscopy images of flat facial pigmented lesions originating from 2 databases. PLP were defined as short, linear, pigmented projections emanating from hair follicles. Dermatoscopy readers were blinded to the final histopathologic diagnosis. From 83 consecutive LMs, 21/83 (25.3%) displayed "bulging of hair follicles" on reflectance confocal microscopy and 18 of these 21 (85.7%), displayed PLP on dermatoscopy. From a database of 2873 consecutively imaged and biopsied lesions, 252 flat-pigmented facial lesions were included. PLP was seen in 47/76 melanomas (61.8%), compared with 7/176 lesions (3.9%) with other diagnosis (P < .001). The sensitivity was 61.8% (95% CI, 49.9%-72.7%), specificity 96.0% (95% CI, 92.9%-98.4%). PLP was independently associated with LM diagnosis on multivariate analysis (OR 26.1 [95% CI, 9.6%-71.0]). Retrospective study. PLP is a newly described dermatoscopic criterion that may add specificity and sensitivity to the early diagnosis of LM located on the face. We postulate that PLP constitutes an intermediary step in the LM progression model.


Fine thermotactic discrimination between the optimal and slightly cooler temperatures via a TRPV channel in chordotonal neurons.
Animals select their optimal environmental temperature, even when faced with alternatives that differ only slightly. This behavior is critical as small differences in temperature of only several degrees can have a profound effect on the survival and rate of development of poikilothermic animals, such as the fruit fly. Here, we demonstrate that Drosophila larvae choose their preferred temperature of 17.5 degrees C over slightly cooler temperatures (14-16 degrees C) through activation of chordotonal neurons. Mutations affecting a transient receptor potential (TRP) vanilloid channel, Inactive (Iav), which is expressed specifically in chordotonal neurons, eliminated the ability to choose 17.5 degrees C over 14-16 degrees C. The impairment in selecting 17.5 degrees C resulted from absence of an avoidance response, which is normally mediated by an increase in turns at the lower temperatures. We conclude that the decision to select the preferred over slightly cooler temperatures requires iav and is achieved by activating chordotonal neurons, which in turn induces repulsive behaviors, due to an increase in high angle turns.


Dexterity, visual perception, and activities of daily living in persons with multiple sclerosis.
ABSTRACT The purposes of this study were to compare dexterity, visual perception, and abilities to carry out activities of daily living (ADL) in persons with different multiple sclerosis (MS) subtypes and to determine what relationships exist between the three variables. Fifty-six persons with MS were administered tests of dexterity, visual perception, and ADL ability. Demographic variables and scores on Kurtzke's Expanded Disability Status Scale were also collected. Scores from the chronic-progressive group were significantly higher than those of the benign and progressive-relapsing groups for the Nine-Hole Peg Test-Left Hand, Grooved Peg Test, and Functional Status Index (except Functional Status Index-Pain). There were no differences between the MS groups for any demographic variables except on the Expanded Disability Status Scale. Visual perception did not correlate with dexterity or ADL ability, and only dexterity scores for the left hand correlated with ADL ability. Persons with the severer subtype of MS were significantly impaired compared with the least severe group for dexterity and ADL ability. Decreased dexterity was associated with needing more assistance and having more perceived difficulty with ADL.


Characterization and mapping of RNase III cleavage sites in VSV genome RNA.
Ribonuclease III cleaves the genome RNA of vesicular stomatitis virus (VSV) to yield an array of fragments which range in size from 3.5 to 0.1 x 10(6) daltons under partial digestion conditions. The locations of the RNase III cleavage sites which give rise to these fragments have been ordered relative to the 3' end of the virion RNA by digestion of 3' end-labeled RNA. Based on a map of the cleavage sites we predicted that fragments having the same size could be generated which contain information from each gene. Annealing of individual VSV mRNA probes to Northern blots of the separated RNase III-generated fragments confirmed that fragments having the same size are, in fact, generated which contain information from each coding region of the VSV genome. Analysis of maps of partial digestion products indicates that fragments having the same size arise repeatedly along the 3' half of the genome. The cleavage of VSV RNA by RNase III can be detected only if the nuclease treated molecules are denatured. This suggest that the structure features in VSV RNA which signal cleavage involve areas of higher order RNA structure.


Anal squamous intraepithelial lesions among HIV positive and HIV negative men who have sex with men in Thailand.
To evaluate the prevalence and risk factors of anal squamous intraepithelial lesions (ASIL), the putative anal cancer precursor, in Asian HIV positive and HIV negative men who have sex with men (MSM). Men who underwent anal Pap smear reported clinical, sociodemographic and behavioural information collected through questionnaire and interview between January 2007 and April 2008. Chi(2) and logistic regression were used to evaluate ASIL prevalence and risk factors among HIV positive and HIV negative MSM. Of the 174 MSM (mean age 32.1 years), 118 (67.8%) were HIV positive. Overall, 27% had abnormal anal cytology: 13.2% had atypical squamous cells of undetermined significance (ASC-US), 11.5% had low-grade squamous intraepithelial lesion (LSIL) and 2.3% had high-grade squamous intraepithelial lesion (HSIL). Prevalence of ASIL was higher among HIV positive than HIV negative MSM (33.9% vs 12.5%; p = 0.003). Among HIV positive MSM, 16.1% had ASC-US, 14.4% had LSIL and 3.4% had HSIL and 7.1%, 5.4% and 0% in HIV negative MSM, respectively. Anal condyloma was detected in 22% of HIV positive and 16.1% (9/56) of HIV negative MSM (p = 0.5). In HIV positive MSM, anal condyloma (OR 3.42, 95% CI 1.29 to 9.04; p = 0.01) was a significant risk factor for ASIL. Highly active antiretroviral therapy use and CD4+ T cell count were not associated with ASIL. One-third of HIV positive and 12.5% of HIV negative MSM had ASIL. Thus, as greater numbers of HIV positive MSM live longer due to increasing access to HAART worldwide, effective strategies to screen and manage anal precancerous lesions are needed.


Functional characterization of a testis-specific DNA binding activity at the H19/Igf2 imprinting control region.
The DNA methylation state of the H19/Igf2 imprinting control region (ICR) is differentially set during gametogenesis. To identify factors responsible for the paternally specific DNA methylation of the ICR, germ line and somatic extracts were screened for proteins that bind to the ICR in a germ line-specific manner. A specific DNA binding activity that was restricted to the male germ line and enriched in neonatal testis was identified. Its three binding sites within the ICR are very similar to the consensus sequence for nuclear receptor extended half sites. To determine if these binding sites are required for establishment of the paternal epigenetic state, a mouse strain in which the three sites were mutated was generated. The mutated ICR was able to establish a male-specific epigenetic state in sperm that was indistinguishable from that established by the wild-type ICR, indicating that these sequences are either redundant or have no function. An analysis of the methylated state of the mutant ICR in the soma revealed no differences from the wild-type ICR but did uncover in both mutant and wild-type chromosomes a significant relaxation in the stringency of the methylated state of the paternal allele and the unmethylated state of the maternal allele in neonatal and adult tissues.


Human astrocytes stimulate HIV-1 expression in a chronically infected promonocyte clone via interleukin-6.
Human promonocyte cells chronically infected with human immunodeficiency virus type (HIV-1) (clone U1.1.5) were grown in the presence of media conditioned by human astrocytes and glioma cell lines U251 and 253. HIV-1 expression was assessed by measuring reverse transcriptase activity. All media conditioned by unstimulated and lipopolysaccharide (LPS) stimulated glial cells induced HIV-1 expression and contained detectable levels of interleukin-6 (IL-6) but not tumor necrosis factor-alpha (TNF-alpha). An antibody against IL-6, but not against TNF-alpha, reduced the induction of HIV-1 by the conditioned media in a concentration-dependent manner. The magnitude of HIV-1 induction by the conditioned media was proportional to the concentration of IL-6 in them. The data indicate that normal and transformed human astrocytes are capable of stimulating HIV-1 expression in chronically infected promonocytic cells by secreting IL-6. The results demonstrate that cytokines secreted by neural cells could play an important role in regulating HIV-1 expression in the brain.


Solution-Processed Donor-Acceptor Polymer Nanowire Network Semiconductors For High-Performance Field-Effect Transistors.
Organic field-effect transistors (OFETs) represent a low-cost transistor technology for creating next-generation large-area, flexible and ultra-low-cost electronics. Conjugated electron donor-acceptor (D-A) polymers have surfaced as ideal channel semiconductor candidates for OFETs. However, high-molecular weight (MW) D-A polymer semiconductors, which offer high field-effect mobility, generally suffer from processing complications due to limited solubility. Conversely, the readily soluble, low-MW D-A polymers give low mobility. We report herein a facile solution process which transformed a lower-MW, low-mobility diketopyrrolopyrrole-dithienylthieno[3,2-b]thiophene (I) into a high crystalline order and high-mobility semiconductor for OFETs applications. The process involved solution fabrication of a channel semiconductor film from a lower-MW (I) and polystyrene blends. With the help of cooperative shifting motion of polystyrene chain segments, (I) readily self-assembled and crystallized out in the polystyrene matrix as an interpenetrating, nanowire semiconductor network, providing significantly enhanced mobility (over 8 cm(2)V(-1)s(-1)), on/off ratio (10(7)), and other desirable field-effect properties that meet impactful OFET application requirements.


Neural Crest-Specific TSC1 Deletion in Mice Leads to Sclerotic Craniofacial Bone Lesion.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in either TSC1 or TSC2. TSC has high frequency of osseous manifestations such as sclerotic lesions in the craniofacial region. However, an animal model that replicates TSC craniofacial bone lesions has not yet been described. The roles of Tsc1 and the sequelae of Tsc1 dysfunction in bone are unknown. In this study, we generated a mouse model of TSC with a deletion of Tsc1 in neural crest-derived (NCD) cells that recapitulated the sclerotic craniofacial bone lesions in TSC. Analysis of this mouse model demonstrated that TSC1 deletion led to enhanced mTORC1 signaling in NCD bones and the increase in bone formation is responsible for the aberrantly increased bone mass. Lineage mapping revealed that TSC1 deficient NCD cells overpopulated the NCD bones. Mechanistically, hyperproliferation of osteoprogenitors at an early postnatal stage accounts for the increased osteoblast pool. Intriguingly, early postnatal treatment with rapamycin, an mTORC1 inhibitor, can completely rescue the aberrant bone mass, but late treatment cannot. Our data suggest that enhanced mTOR signaling in NCD cells can increase bone mass through enlargement of the osteoprogenitor pool, which likely explains the sclerotic bone lesion observed in TSC patients.


Effect of the crp mutation on the utilization of transferrin-bound iron by Vibrio vulnificus.
Cyclic AMP-cAMP receptor protein (CRP) complex plays an essential role in the global regulation of Vibrio vulnificus virulence. We found that growth retardation of V. vulnificus caused by mutation of the crp gene encoding CRP was exacerbated under iron-limited conditions. Accordingly, we investigated the effect of crp mutation on the expression of the vulnibactin-mediated iron-uptake system and the ability of V. vulnificus to utilize transferrin-bound iron, and thus to grow in cirrhotic ascites, a human ex vivo system. The production of vulnibactin was suppressed, and the transcription of the vis and vuuA genes, which encode an enzyme required for vulnibactin synthesis and vulnibactin receptor protein, was also suppressed in the crp mutant. Moreover, the crp mutant could not utilize transferrin-bound iron, and its growth was severely suppressed both on transferrin-bound iron and in cirrhotic ascites. All the defects in the crp mutant were recovered by the in trans complementation of the wild-type crp gene. Putative CRP-binding sequences were found in the regulatory regions of the fur, vis and vuuA genes. These results indicate that crp mutation attenuates the ability to grow on transferrin-bound iron and in a human body fluid by down-regulating the vulnibactin-mediated iron-uptake system.


Enhancement of attraction and trap catches of the old-house borer, Hylotrupes bajulus (Coleoptera: Cerambycidae), by combination of male sex pheromone and monoterpenes.
Monoterpenoid compounds extracted from wood of Scots pine, Pinus sylvestris L, synergized the attraction of the old-house borer, Hylotrupes bajulus (L), to the male pheromone (3R)-3-hydroxy-2-hexanone ((3R)-ketol) + 1-butanol. Glasshouse experiments using ground traps baited with extracts derived from Scots pine wood or the monoterpenes (+)-alpha-pinene, (-)-verbenone, (-)-trans-pinocarveol and (+)-terpinen-4-ol attracted significantly more H bajulus females, but caught fewer of them, than the synthetic pheromone mixture alone. Traps baited with higher concentrations of the monoterpene mixture attracted fewer females than those baited with lower dosages, whilst very high concentrations of the mixture (6-10 vials) caught no insects. However, a combination of (3R)-ketol + 1-butanol or (+/-)-3-ketol + 1-butanol with monoterpenes resulted in the capture of significantly more females than either the sex pheromone or the monoterpene mixture alone. Traps baited with a blend of the male's sex pheromone or the monoterpenes attracted significantly more, but caught fewer, males than females. Here again, a combination of the above blends enhanced the attraction of males significantly when compared with the attractancy of either of the compounds/mixtures used alone.


Using Smartphone Apps to Promote Psychiatric and Physical Well-Being.
This pilot study tested the acceptability and usability of a prototype app designed to promote the physical well-being of adults with psychiatric disorders. The application under evaluation, WellWave, promoted walking as a physical exercise, and offered a variety of supportive non-physical activities, including confidential text-messaging with peer staff, and a digital library of readings and videos on recovery from psychiatric illness. Study participants engaged strongly in the app throughout the 4-week study, showing a 94 % mean daily usage rate, and a 73 % mean response rate across all electronic messages and prompts, which approximates the gold standard of 75 % for momentary ecological assessment studies. Seven of the ten study participants averaged two or more walks per week, beginning with 5-min walks and ending with walks lasting 20 min or longer. This responsiveness to the walking prompts, and the overall high rate of engagement in other app features, suggest that adults with psychiatric conditions would welcome and benefit from similar smartphone interventions that promote healthy behaviours in life domains other than exercise. Pilot study results also suggest that smartphone applications can be useful as research tools in the development and testing of theories and practical strategies for encouraging healthy lifestyles. Participants were prompted periodically to rate their own health quality, perceived control over their health, and stage-of-change in adopting a walking routine, and these electronic self-ratings showed acceptable concurrent and discriminant validity, with all participants reporting moderate to high motivation to exercise by the end of the study.


Instructional treatment associated with changes in brain activation in children with dyslexia.
To assess the effects of reading instruction on fMRI brain activation in children with dyslexia. fMRI differences between dyslexic and control subjects have most often involved phonologic processing tasks. However, a growing body of research documents the role of morphologic awareness in reading and reading disability. The authors developed tasks to probe brain activation during phoneme mapping (assigning sounds to letters) and morpheme mapping (understanding the relationship of suffixed words to their roots). Ten children with dyslexia and 11 normal readers performed these tasks during fMRI scanning. Children with dyslexia then completed 28 hours of comprehensive reading instruction. Scans were repeated on both dyslexic and control subjects using the same tasks. Before treatment, children with dyslexia showed less activation than controls in left middle and inferior frontal gyri, right superior frontal gyrus, left middle and inferior temporal gyri, and bilateral superior parietal regions for phoneme mapping. Activation was significantly reduced for children with dyslexia on the initial morpheme mapping scan in left middle frontal gyrus, right superior parietal, and fusiform/occipital region. Treatment was associated with improved reading scores and increased brain activation during both tasks, such that quantity and pattern of activation for children with dyslexia after treatment closely resembled that of controls. The elimination of group differences at follow-up was due to both increased activation for the children with dyslexia and decreased activation for controls, presumably reflecting practice effects. These results suggest that behavioral gains from comprehensive reading instruction are associated with changes in brain function during performance of language tasks. Furthermore, these brain changes are specific to different language processes and closely resemble patterns of neural processing characteristic of normal readers.


Affective disorders and cognitive failures: a comparison of seasonal and nonseasonal depression.
Seasonal depression shares certain common symptoms with nonseasonal depression; however, the two disorders have never been examined in a single study, to the authors' knowledge. The goal of this research was to examine the potential similarities in cognitive impairments in seasonal affective disorder and major depressive disorder in college students in the Midwest. Identification of affective disorders was based on participants' self-reported behavior and affect on the Beck Depression Inventory and the Seasonal Pattern Assessment Questionnaire. A group of 93 participants was assessed for major depressive disorder and seasonal affective disorder in late autumn and completed the Cognitive Failures Questionnaire for reported difficulties in everyday activities that correspond to problems with perception, attention, and memory retrieval. The results indicated that seasonal affective disorder was highly prevalent (28.0%), substantially more so than major depressive disorder (8.6%). Similar to previous research on major depressive disorder, gender differences were also evident among participants with seasonal affective disorder, with more women qualifying than men. Both affective disorders were associated with higher reports of cognitive failures in comparison to participants with no depressive symptoms. These results reveal that individuals with seasonal affective disorder showed cognitive impairments similar to those with nonseasonal depression.


Ramucirumab plus atezolizumab in patients with stage IV non-small cell lung cancer previously treated with immune checkpoint inhibitors.
The treatment options for patients with stage IV non-small cell lung cancer (NSCLC) who develop tumor progression after platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) are limited. The combination of ICI with inhibitors of vascular endothelial growth receptor (VEGFR) signaling has shown promising results in previously untreated patients. In this single institution phase II study, patients with advanced stage NSCLC previously treated with at least one line including ICI received ramucirumab 10 mg/kg and atezolizumab 1,200 mg intravenously every 21 days until tumor progression or intolerable toxicity. The primary endpoint was overall response rate (ORR) by the RECIST 1.1 criteria according to the investigator assessment. Secondary endpoints included clinical benefit rate (CBR), overall survival (OS), progression-free survival (PFS) and tolerability. Twenty-one patients were enrolled between June 2019 and April 2021. The median age was 67 (range 42-82), 17 (81 %) were female, and 15 (71 %) had non-squamous histology. The median number of prior systemic treatment lines and prior ICI lines were 3 (range 2-8) and 1 (range 1-3), respectively. One patient achieved a complete response for an ORR of 4.8 % while 16 (76.2 %) had stable disease with a CBR of 80.9 %. The median PFS was 3.4 months, and the median OS was 16.5 months. The most common adverse events included hypertension (86 %), proteinuria (67 %), and nausea (52 %). Grade 3 or 4 events were seen in 9 (43 %) of patients, with hypertension being the most common (33 %) of the grade 3 or 4 events. Although the primary endpoint of ORR was not met, the combination of ramucirumab plus atezolizumab was associated with a high CBR and the OS was better than expected in heavily pretreated patients. Therefore, further investigation with ICI plus VEGF inhibition is warranted.


Bit-error rate for free-space adaptive optics laser communications.
An analysis of adaptive optics compensation for atmospheric-turbulence-induced scintillation is presented with the figure of merit being the laser communications bit-error rate. The formulation covers weak, moderate, and strong turbulence; on-off keying; and amplitude-shift keying, over horizontal propagation paths or on a ground-to-space uplink or downlink. The theory shows that under some circumstances the bit-error rate can be improved by a few orders of magnitude with the addition of adaptive optics to compensate for the scintillation. Low-order compensation (less than 40 Zernike modes) appears to be feasible as well as beneficial for reducing the bit-error rate and increasing the throughput of the communication link.


Inhibition of Ferroptosis Ameliorates Photoreceptor Degeneration in Experimental Diabetic Mice.
Diabetic retinopathy (DR) is a leading cause of vision impairment in the working-age population worldwide. Various modes of photoreceptor cell death contribute to the development of DR, including apoptosis and autophagy. However, whether ferroptosis is involved in the pathogenesis of photoreceptor degeneration in DR is still unclear. High-glucose (HG)-stimulated 661W cells and diabetic mice models were used for in vitro and in vivo experiments, respectively. The levels of intracellular iron, glutathione (GSH), reactive oxygen species (ROS), lipid peroxidation (MDA), and ferroptosis-related proteins (GPX4, SLC7A11, ACSL4, FTH1, and NCOA4) were quantified to indicate ferroptosis. The effect of ferroptosis inhibition was also assessed. Our data showed the levels of iron, ROS, and MDA were enhanced and GSH concentration was reduced in HG-induced 661W cells and diabetic retinas. The expression of GPX4 and SLC7A11 was downregulated, while the expression of ACSL4, FTH1, and NCOA4 was upregulated in the 661W cells cultured under HG conditions and in the photoreceptor cells in diabetic mice. Furthermore, the administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1) obviously alleviated ferroptosis-related changes in HG-cultured 661W cells and in retinal photoreceptor cells in diabetic mice. Taken together, our findings suggest that ferroptosis is involved in photoreceptor degeneration in the development of the early stages of DR.


A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis.
To evaluate the safety and efficacy of an enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule, after 1, 3, and 6 months. This was a randomised, placebo controlled, double blind, escalating dose multicentre study in 40 patients with mild to moderately active distal ulcerative colitis (disease activity index (DAI) 4-10). Patients were assigned to four dosing cohorts of 10 patients each (eight active, two placebo). Each patient received 60 ml of alicaforsen enema (0.1, 0.5, 2, or 4 mg/ml or placebo) once daily for 28 consecutive days. Safety and efficacy (DAI and clinical activity index) scores were evaluated up to six months after initiation of dosing. At day 29, alicaforsen enema resulted in dose dependent improvement in DAI (overall p = 0.003). Alicaforsen 4 mg/ml improved DAI by 70% compared with the placebo response of 28% (p = 0.004). Alicaforsen 2 and 4 mg/ml improved DAI status by 72% and 68% compared with a placebo response of 11.5% at month 3 (p = 0.016 and 0.021, respectively). Specifically, DAI improved from 5.6 to 1.6 and from 6.3 to 2.5 in the 2 and 4 mg/ml groups compared with placebo (7.5 to 6.1). None of the patients in the 4 mg/ml group compared with 4/8 placebo patients required additional medical or surgical intervention over baseline during the six month period after starting the enema treatment. The safety profile was favourable. Alicaforsen enema showed promising acute and long term benefit in patients with mild to moderate descending ulcerative colitis. Alicaforsen enemas had a favourable safety profile. These findings require verification in larger randomised controlled clinical trials.


In search of pathogens: transcriptome-based identification of viral sequences from the pine processionary moth (Thaumetopoea pityocampa).
Thaumetopoea pityocampa (pine processionary moth) is one of the most important pine pests in the forests of Mediterranean countries, Central Europe, the Middle East and North Africa. Apart from causing significant damage to pinewoods, T. pityocampa occurrence is also an issue for public and animal health, as it is responsible for dermatological reactions in humans and animals by contact with its irritating hairs. High throughput sequencing technologies have allowed the fast and cost-effective generation of genetic information of interest to understand different biological aspects of non-model organisms as well as the identification of potential pathogens. Using these technologies, we have obtained and characterized the transcriptome of T. pityocampa larvae collected in 12 different geographical locations in Turkey. cDNA libraries for Illumina sequencing were prepared from four larval tissues, head, gut, fat body and integument. By pooling the sequences from Illumina platform with those previously published using the Roche 454-FLX and Sanger methods we generated the largest reference transcriptome of T. pityocampa. In addition, this study has also allowed identification of possible viral pathogens with potential application in future biocontrol strategies.


Use of synthetic communities to study microbial ecology of the gut.
The application of in vitro synthetic microbial communities is an excellent approach to model the ecological interactions between microbes in the human gastrointestinal tract. Although DNA-based studies have provided a wealth of information, they do not consider the ecological properties of the human gut microbiota. Ecological interactions between gut microbes of interest can be studied by applying synthetic communities. This review describes the considerations that should be taken into account when constructing a synthetic community by discussing example research questions that can be answered by using a synthetic microbial community, the choice of microbial species, the growth conditions, possible reactor setups, and the parameters to analyze.


Stellate Cell Networks in the Teleost Pituitary.
The folliculostellate cells of the mammalian pituitary are non-endocrine cells that are implicated in long-distance communication and paracrine signaling, but to date, these cells have yet to be characterized in teleosts. We found that the stellate cells of the teleost pituitary share many common attributes with mammalian folliculostellate cells. By labeling of stellate cells in live preparations of tilapia pituitaries we investigated their distribution, association with other endocrine cells and their anatomical and functional coupling. In the pars intermedia, stellate cells were arranged around neuronal bundles and their processes extended into the pars distalis. Within the pars distalis, stellate cells formed close associations with FSH cells and, to a lesser degree, with GH and LH cells, suggesting differential paracrine regulation of the two gonadotrope populations. The production of follistatin by stellate cells further corroborates the notion of a paracrine role on FSH release. We also found stellate cells to form gap junctions that enabled dye transfer to neighboring stellate cells, implicating that these cells form a large-scale network that connects distant parts of the pituitary. Our findings represent the first wide-scale study of stellate cells in teleosts and provide valuable information regarding their functional roles in pituitary function.


Physical activity and cancer prevention: awareness and meeting the recommendations among adult Saudis.
There is a scarcity of information about the proportion of the adult Saudi population that meet the recommended guidelines of physical activity (PA) to reduce cancer risk. Moreover, their awareness about the role of PA in cancer prevention is unclear. This cross-sectional study aimed at estimating the proportion of adult Saudis meeting the PA guidelines, specifically those recommended by American Cancer Society (ACS) for cancer prevention, and to assess the public awareness about the role of PA in cancer prevention. Using a multistage sampling method, 2,127 adult Saudis of both genders were recruited from 6 urban and 4 rural primary health care centers in Al Hassa, Saudi Arabia. Participants were personally interviewed to gather information about their sociodemographic characteristics, searching activity about PA and cancer, and the time spent in leisure time PA (moderate and vigorous)/week using the Global Physical Activity Questionnaire with show cards. Finally, items about the role of PA in cancer risk reduction were inquired. Of the included participants, 11.6% met the recommendations for cancer prevention (≥ 45 minutes of moderate-vigorous PA activity/≥ 5 days/week or 225 minutes/week). Multivariate regression showed that being male (AOR=1.49, CI=1.09-2.06), <20 years of age (AOR=3.11, CI=2.03-4.76), and unemployed (AOR=2.22, CI=1.57-3.18) were significant predictors for meeting PA recommendations for cancer prevention. Only 11.4% of the sample indicated correctly the frequency and duration of PA required for an average adult to be physically active and while >70% of them indicated the role of PA in prevention of hypertension, coronary heart disease and lowering elevated blood cholesterol, only 18.6% and 21.7% correctly mentioned the role of PA in reducing colon and breast cancer risk, respectively. Poor knowledge was found among those with less than college education and aged ≥ 50 years. The level of knowledge was significantly positively correlated with total leisure time PA of the participants. A minority of adult Saudis in Al Hassa was aware about the role of PA in cancer prevention and engaged in sufficient LTPA for cancer risk reduction benefits, highlighting the need for public health actions to include policies and programs that address factors deterring their participation in LTPA and increasing their awareness with remedies to manage the prevalent misconceptions.


Inhibition of miR-27b Regulates Lipid Metabolism in Skeletal Muscle of Obese Rats During Hypoxic Exercise by Increasing PPARγ Expression.
Hypoxic exercise may represent a novel therapeutic strategy to reduce and prevent obesity through the regulation of lipid metabolism. During hypoxic exercise, the targeting of peroxisome proliferator-activated receptor gamma (PPARγ) by miR-27b has been proposed to be one of the mechanisms involved in the modulation of lipid metabolism. We have previously shown that miR-27b can repress PPARγ and lipid metabolism-associated factors, thereby affecting lipid metabolism during hypoxic exercise in a rat model of obesity. In the current study, we aimed to confirm the role of miR-27b in the regulation of lipid metabolism. First, miR-27b expression was either upregulated or downregulated through the injection of adeno-associated virus (AAV) 9 containing a miR-27b expression cassette or miR-27b-3p inhibitor, respectively, into the right gastrocnemius muscle of obese rats. The rats were then subjected to a 4-week program of hypoxic exercise, and a series of parameters related to lipid metabolism were systematically evaluated, including body composition, blood lipid levels, miR-27b RNA levels, and mRNA and protein levels of PPARγ and those of its downstream lipid metabolism-associated factors. No significant differences were found in body composition between rats expressing different levels of miR-27b. However, regarding blood lipids, miR-27b overexpression led to increased concentrations of triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and free fatty acids (FFAs), while inhibition of miR-27b decreased the total cholesterol (TC) level and increased that of high-density lipoprotein cholesterol (HDL-C). At the mRNA level, miR-27b overexpression downregulated the expression of Pparγ, but upregulated that of lipid metabolism-associated factors such as heart-type fatty acid-binding protein (H-FABP), fatty acid transport protein 1 (FATP1), adipose triglyceride lipase (ATGL), and lipoprotein lipase (LPL), whereas miR-27b inhibition elicited the opposite effect; however, inhibition of miR-27b led to elevated cholesterol 7 alpha-hydroxylase (CYP7A1) and fatty acid translocase 36 (CD36) levels. Similarly, at the protein level, miR-27b overexpression promoted a decrease in the concentration of PPARγ, whereas miR-27b inhibition led to an increase in PPARγ levels, as well as those of CYP7A1, CD36, ATGL, and LPL. Overall, our results indicated that hypoxic exercise regulates lipid metabolism via the miR-27b/PPARγ pathway and modulates ATGL and LPL expression through inducing their post-transcriptional modifications.


Dietary patterns and cognitive dysfunction in a 12-year follow-up study of 70 year old men.
Adherence to dietary patterns has been associated with cognitive decline and dementia, but studies are inconsistent. Dietary patterns, i.e., WHO recommendations (Healthy Diet Indicator), a Mediterranean-like diet (modified Mediterranean Diet Score, mMDS), and a low carbohydrate high protein diet (LCHP), were related to incident cognitive dysfunction, as indicated by Alzheimer's disease (AD), all-type dementia, and all-type cognitive impairment, in a cohort of 1,138 elderly Swedish men. Dietary patterns were derived from 7-day records. Risk relations were calculated by Cox and logistic regression analyses, adjusted for potential confounders. Sensitivity analysis was performed in a subpopulation (n = 564) with energy intake according to the Goldberg cut-off. During a mean follow-up of 12 years, 84, 143, and 198 men developed AD, all-type dementia, and all-type cognitive impairment, respectively. There was no association between Healthy Diet Indicator and any of the outcomes. Hazard ratios associated with 1 standard deviation (SD) increment in the LCHP score were 1.16 (95% confidence interval [CI]: 0.95, 1.43) for AD and 1.16 (95% CI: 0.99, 1.37) for all-type dementia. mMDS was not associated with dementia diagnosis. Odds ratio (OR)/1 SD increase for mMDS and all-type cognitive impairment was 0.82 (95% CI: 0.65, 1.05). In the subpopulation OR for mMDS and all-type cognitive impairment was 0.32 (95% CI: 0.11, 0.89). We found no strong associations with development of cognitive dysfunction for any of the dietary patterns investigated. However, there was a potentially beneficial association for a Mediterranean-like diet on the development of cognitive dysfunction in the subpopulation.


Connective tissue activation XXVI: IgG stimulation of glycosaminoglycan synthesis in human synovial cultures.
Substances known to enhance synthesis of glycosaminoglycans (GAG) in human synovial fibroblast cultures include "Connective Tissue Activating Peptides" (CTAP) isolated from certain organs, leukocytes and platelets as well as cyclic AMP and specific prostaglandins. This report shows that immunoglobulin G (IgG) isolated from 7 mammalian sources, including human, stimulated GAG production by human synovial cultures 3 to 18 fold. IgG generally did not stimulate DNA synthesis by human synovial fibroblasts as determined by [3H]-thymidine uptake. On a molar basis, IgG had a specific activity similar to that of CTAP-Ib(spleen) and CTAP-III (platelets). Normal human plasma levels of IgG may be sufficient to provide additional stimulus for activation of synovial connective tissue during the inflammatory response.


Mechanism of polaritons coupling from perspective of equivalent MLC circuits model in slit arrays.
Magnetic polariton is a significant mode in tailoring thermal radiative properties with micro/nanostructures metamaterials and can be explained by equivalent inductor-capacitor circuit model. However, the equivalent inductor-capacitor circuit model is out of operation when the magnetic polariton resonance frequency is close to the surface plasmon polariton excitation frequency and cases of oblique incidence. In this work, we present a mutual inductor-inductor-capacitor circuit model to describe magnetic polariton resonance conditions. The mechanism of coupling between the surface plasmon polariton and magnetic polariton is explained from the perspective of equivalent circuits. The interaction between the surface plasmon polariton and magnetic polariton is studied and considered as a mutual inductance in the MLC circuit model. This model is still applicable in the case of oblique incidence. Slit arrays with different geometric parameters and incident angles are calculated to verify the rationality of the mutual inductor-inductor-capacitor circuit model. This study may allow us to predict features and parameters and achieve tailoring of the thermal radiative properties of the micro/nano-structures metamaterials.


A look at the potential association between PICOT framing of a research question and the quality of reporting of analgesia RCTs.
Methodologists have proposed the formation of a good research question to initiate the process of developing a research protocol that will guide the design, conduct and analysis of randomized controlled trials (RCTs), and help improve the quality of reporting such studies. Five constituents of a good research question based on the PICOT framing include: Population, Intervention, Comparator, Outcome, and Time-frame of outcome assessment. The aim of this study was to analyze if the presence a structured research question, in PICOT format, in RCTs used within a 2010 meta-analysis investigating the effectiveness of femoral nerve blocks after total knee arthroplasty, is independently associated with improved quality of reporting. Twenty-three RCT reports were assessed for the quality of reporting and then examined for the presence of the five constituents of a structured research question based on PICOT framing. We created a PICOT score (predictor variable), with a possible score between 0 and 5; one point for every constituent that was included. Our outcome variable was a 14 point overall reporting quality score (OQRS) and a 3 point key methodological items score (KMIS) based on the proper reporting of allocation concealment, blinding and numbers analysed using the intention-to-treat principle. Both scores, OQRS and KMIS, are based on the Consolidated Standards for Reporting Trials (CONSORT) statement. A multivariable regression analysis was conducted to determine if PICOT score was independently associated with OQRS and KMIS. A completely structured PICOT score question was found in 2 of the 23 RCTs evaluated. Although not statistically significant, higher PICOT was associated with higher OQRS [IRR: 1.267; 95% confidence interval (CI): 0.984, 1.630; p = 0.066] but not KMIS (1.061 (0.515, 2.188); 0.872). These results are comparable to those from a similar study in terms of the direction and range of IRRs estimates. The results need to be interpreted cautiously due to the small sample size. This study showed that PICOT framing of a research question in anesthesia-related RCTs is not often followed. Even though a statistically significant association with higher OQRS was not found, PICOT framing of a research question is still an important attribute within all RCTs.


Association of Race and Ethnicity and Medicare Program Type With Ambulatory Care Access and Quality Measures.
There are racial inequities in health care access and quality in the United States. It is unknown whether such differences for racial and ethnic minority beneficiaries differ between Medicare Advantage and traditional Medicare or whether access and quality are better for minority beneficiaries in 1 of the 2 programs. To compare differences in rates of enrollment, ambulatory care access, and ambulatory care quality by race and ethnicity in Medicare Advantage vs traditional Medicare. Exploratory observational cohort study of a nationally representative sample of 45 833 person-years (26 887 persons) in the Medicare Current Beneficiary Survey from 2015 to 2018, comparing differences in program enrollment and measures of access and quality by race and ethnicity. Minority race and ethnicity (Black, Hispanic, Native American, or Asian/Pacific Islander) vs White or multiracial; Medicare Advantage vs traditional Medicare enrollment. Six patient-reported measures of ambulatory care access (whether a beneficiary had a usual source of care in the past year, had a primary care clinician usual source of care, or had a specialist visit) and quality (influenza vaccination, pneumonia vaccination, and colon cancer screening). The final sample included 6023 persons (mean age, 68.9 [SD, 12.6] years; 57.3% women) from minority groups and 20 864 persons (mean age, 71.9 [SD, 10.8] years; 54.9% women) from White or multiracial groups, who accounted for 9816 and 36 017 person-years, respectively. Comparing Medicare Advantage vs traditional Medicare among minority beneficiaries, those in Medicare Advantage had significantly better rates of access to a primary care clinician usual source of care (79.1% vs 72.5%; adjusted marginal difference, 4.0%; 95% CI, 1.0%-6.9%), influenza vaccinations (67.3% vs 63.0%; adjusted marginal difference, 5.2%; 95% CI, 1.9%-8.5%), pneumonia vaccinations (70.7% vs 64.6%; adjusted marginal difference, 6.1%; 95% CI, 2.7%-9.4%), and colon cancer screenings (69.4% vs 61.1%; adjusted marginal difference, 7.1%; 95% CI, 3.8%-10.3%). Comparing minority vs White or multiracial beneficiaries across both programs, minority beneficiaries had significantly lower rates of access to a primary care clinician usual source of care (adjusted marginal difference, 4.7%; 95% CI, 2.5%-6.8%), specialist visits (adjusted marginal difference, 10.8%; 95% CI, 8.3%-13.3%), influenza vaccinations (adjusted marginal difference, 4.3%; 95% CI, 1.2%-7.4%), and pneumonia vaccinations (adjusted marginal difference, 6.4%; 95% CI, 3.9%-9.0%). The interaction of race and ethnicity with insurance type was not statistically significant for any of the 6 outcome measures. In this exploratory study of Medicare beneficiaries in 2015-2018, enrollment in Medicare Advantage vs traditional Medicare was significantly associated with better outcomes for access and quality among minority beneficiaries; however, minority beneficiaries were significantly more likely to experience worse outcomes for most access and quality measures than White or multiracial beneficiaries in both programs.


When, If Ever, Is It Appropriate to Regard a Patient as "Too Medically Complex" for One Inpatient Service, But Not Another?
Patients with chronic health conditions often find their admission for orthopedic surgery from the emergency department held up due to disagreement between orthopedists and internal medicine physicians, such as hospitalists. One reason for this delay is that orthopedists must decide which patients they will admit. Although this decision is based on clinical criteria, variation in orthopedists' practices and views of a patient's condition's medical complexity is a common source of physician disagreement. This commentary on a case describes constraints on hospitalists and orthopedists, as well as other factors in patient disposition, and suggests quality improvements to admissions processes that might help mitigate the distress that patients can experience as a result of health professional disagreement.


An interfaculty pain curriculum: lessons learned from six years experience.
Minimal pain content has been documented in pre-licensure curricula and students lack important pain knowledge at graduation. To address this problem, we have implemented and evaluated a mandatory Interfaculty Pain Curriculum (IPC) yearly since 2002 for students (N=817 in 2007) from six Health Science Faculties/Departments. The 20-h pain curriculum continues to involve students from Dentistry, Medicine, Nursing, Pharmacy, Physical Therapy, and Occupational Therapy as part of their 2nd or 3rd year program. Evaluation methods based on Kirkpatrick's model now include evaluation of a Comprehensive Pain Management Plan along with the previously used Pain Knowledge and Beliefs Questionnaire (PKPQ) and Daily Content and Process Questionnaires (DCPQ). Important lessons have been learned and subsequent changes made in this iterative curriculum design based on extensive evaluation over the 6-year period. Modifications have included case development more relevant to the diverse student groups, learning contexts that are uni-, inter-, and multi-professional, and facilitator development in working with interprofessional student groups. PKBQ scores have improved in all years with a statistically significant average change on correct responses from 14% to 17%. The DCPQ responses have also indicated consistently that most students (85-95%) rated highly the patient panel, expert-lead clinically focused sessions, and small interprofessional groups. Relevancy and organization of the information presented have been generally rated highly from 80.3% to 91.2%. This curriculum continues to be a unique and valuable learning opportunity as we utilize lessons learned from extensive evaluation to move the pain agenda forward with pre-licensure health science students.


Corneal density with the Pentacam after photorefractive keratectomy.
To measure corneal density and evaluate corneal haze in unoperated eyes and in eyes after photorefractive keratectomy (PRK). Forty-nine patients (91 eyes) who underwent PRK and 48 control patients (76 unoperated eyes) were measured with the densitometry program of the Pentacam Scheimpflug imaging system (Oculus Optikgeräte GmbH) (0=no clouding, 100=tissue completely opaque). Eyes were categorized as myopic or hyperopic (myopia group and hyperopia group), with subgroups defined as unoperated (unoperated myopia group and unoperated hyperopia group), postoperative clear corneas (clear cornea myopia group and clear cornea hyperopia group), and postoperative with haze (myopia haze group and hyperopia haze group). The ANOVA option of the Statistica 8.1 program package (StatSoft Inc) was used to compare subgroups. Maximum density of postoperative corneas with haze (myopia haze group, 46.2±16.2; hyperopia haze group, 50.2±25.8) was higher than in postoperative clear corneas (clear cornea myopia group, 29.9±8.7; clear cornea hyperopia group, 22.9±3.1), but maximum corneal density in the latter subgroups showed no difference compared with unoperated controls (unoperated myopia group, 25.1±2.4; unoperated hyperopia group, 22.8±3.2). Differences among subgroups were not found outside the 6-mm diameter ablation zone. In hazy myopic corneas, there was a strong decreasing density trend from the apex to the 3-mm radius (P<.001, R=-0.5), which continued towards the periphery at 4.5 mm (P=.019, R=-0.21). Hyperopic mild hazy corneas showed a density increase from the apex to 3 mm (P<.001, R=0.4), followed by a decrease towards the periphery (P<.01, R=-0.4). The densitometry program of the Pentacam can provide a useful objective measure of postoperative and other mild corneal haze.


T cell control of SARS-CoV-2: When, which, and where?
Efficient immune protection against viruses such as SARS-CoV-2 requires the coordinated activity of innate immunity, B and T cells. Accumulating data point to a critical role for T cells not only in the clearance of established infection, but also for aborting viral replication independently of humoral immunity. Here we review the evidence supporting the contribution of antiviral T cells and consider which of their qualitative features favour efficient control of infection. We highlight how studies of SARS-CoV-2 and other coronaviridae in animals and humans have provided important lessons on the optimal timing (When), functionality and specificity (Which), and location (Where) of antiviral T cells. We discuss the clinical implications, particularly for the development of next-generation vaccines, and emphasise areas requiring further study.


Erythropoietin deficiency and anaemia in multiple system atrophy.
Serum erythropoietin (EPO) levels are partially controlled by the sympathetic outflow to the kidney. We have studied whether patients with multiple system atrophy (MSA), known to be associated with dysautonomia, are EPO-deficient. Eighteen MSA patients were studied along with 32 idiopathic Parkinson's disease (PD) patients, 23 controls with iron-deficiency anaemia, and 18 healthy individuals. Serum creatinine was normal in all groups. Mean haemoglobin (Hb) concentration in MSA patients was 13.7 +/- 1.7 g/dL. Four MSA patients had unexplained anaemia (minimum Hb: 10.5 g/dL) and abnormal autonomic function tests including significant postural hypotension, whereas none of the PD patients was anaemic. Serum EPO levels were suppressed in relation to anaemia in MSA patients compared to elevated EPO levels in iron-deficiency anaemia patients (difference of regression lines P < 0.001), indicating EPO deficiency in the anaemic MSA patients. Serum EPO levels in PD patients were within normal range. A subset of MSA patients has anaemia and postural hypotension, which may be associated with EPO deficiency. This may have therapeutic implications.


Cancer/testis antigen HCA587-derived long peptide vaccine generates potent immunologic responses and antitumor effects in mouse model.
The cancer/testis antigen HCA587 (also known as MAGE-C2), one of the most immunogenic tumor antigens, is overexpressed in a wide spectrum of malignant tumors and can serve as a target for immunotherapy. In this study, we synthesized 14 overlapping (25-35 amino acids) long peptides representing the sequence of the most immunogenic part of the HCA587 protein and evaluated the antigen-specific immune responses and antitumor effects generated by immunization with the synthetic long peptide (SLP) vaccine in a mouse model. HCA587 SLPs in combination with adjuvants CFA and CpG ODN induced potent T-cell responses, which were dominated by type 1 cytokine IFN-γ-producing CD4(+) T cells as measured by ELISPOT and intracellular cytokine staining assay. Moreover, HCA587 SLP vaccination conferred protection against challenge with HCA587-expressing B16 melanoma in a therapeutic setting. Our findings may provide a scientific basis for the use of HCA587-derived long overlapping peptide vaccine for the treatment of patients with cancer in future clinical trials.